Huntington's disease (HD) is a hereditary neurodegenerative disease that results in pervasive neuronal dysfunction and death, particularly in the medium spiny neurons of the striatum. There are currently no disease-modifying therapies for HD. A pathological hallmark of HD is accumulation and aggregation of mutant huntingtin protein (mHTT), ultimately resulting in intranuclear and cytoplasmic inclusions within neurons and neurite processes. While the role of aggregation in HD progression is not clear, mHTT aggregation is a marker of disease. Chaperones that assist in the folding of newly synthesized proteins and refold misfolded proteins are intriguing candidate therapeutics to target mHTT aggregation in vivo. CCT1, a subunit of a chaperone complex that binds and folds proteins during de novo protein synthesis, can modulate aggregation and toxicity mediated by a fragment of mHTT. Just the apical domain of CCT1, ApiCCT1, can modulate aggregation in vitro and binds the first 17 AAs of HTT. We find that exogenous delivery of ApiCCT1 decreases aggregation of mHTT and reduces mHTT-mediated toxicity in cell models of HD, making ApiCCT1 a promising therapeutic for HD. In this proposal we provide a strategy to further investigate the cellular effects of ApiCCT1 on mHTT aggregation, evaluate the in vivo potential of ApiCCT1 delivery, and examine continuous delivery of sApiCCT1 by stem cells as a novel disease-modifying therapy option for HD. Specific Aim 1: Investigate mechanism by which ApiCCT1 modulates mHTT aggregation species. The reduction of mHTT aggregation ApiCCT1 may be mediated by multiple pathways. The goal of this aim is to examine mechanisms of ApiCCT1 action to inform the use of ApiCCT1 as a potential therapy. Specific Aim 2: Examine potential of ApiCCT1 as a therapeutic agent and test effects on aggregation in vivo. These experiments will test ApiCCT1 effects on aggregation in vivo, support mechanistic studies, and examine the potential of continuous ApiCCT1 delivery as a therapeutic approach. Specific Aim 3: Determine efficacy of stem cell mediated delivery of ApiCCT1 on HD phenotypes. Cell-based approaches to deliver therapeutic molecules and also provide multiple therapeutic activities themselves may provide a more effective method. Therefore, we propose to investigate a stem cell-based therapeutic strategy to provide continuous delivery of ApiCCT1 to the striatum. These experiments will indicate if combining neurotrophic support with ApiCCT1 delivery is sufficient to improve biochemical and behavioral outcome measures. A combination therapy of this kind has the potential to greatly influence clinical treatment of HD. We hypothesize that delivery of ApiCCT1 will modulate HD phenotypes by preventing aggregation and facilitating mHTT degradation and that stem cell delivery of sApiCCT1 will provide additional neuroprotection, thus offering the potential for a novel disease-modifying HD therapy.